Cardiac resynchronization therapy (CRT) by bi-ventricular pacing has been an important treatment advance for patients with advanced heart failure (HF). It is estimated that there were >150,000 CRT devices implanted in North America in 2007 at an initial cost of ~1-3 billion dollars, with much higher post implantation costs. However, nearly 30% of subjects are considered non or poor responders. While this may be due to problems with patient selection, this may also suggest problems of optimization of atrioventricular (AV) and interventricular (V-V) intervals of the CRT devices. Current selection criteria for CRT are limited to LVEF <35%, QRS duration >120 ms, and refractory NYHA class III-IV symptoms despite optimized pharmacotherapy. However, it is clear that more individualized and physiologically based approaches are needed to improve response rates. Low level physical activity challenges (stresses) the heart through increased metabolic demands, altered systemic venous return, influences on cardiac pre and after load and in HF may enhance ventricular interdependence. The lungs lie in series with the heart, share a common surface area and are intimately linked hemodynamically as well as neuro-mechanically and thus measures of breathing pattern and gas exchange particularly during a mild cardiac load provide a dynamic window of integrated cardiopulmonary function. It is the premise of this proposal that low level, non-invasive cardiopulmonary exercise provides a novel approach for determining which HF patients may be most likely to benefit from CRT and individualizing and optimizing CRT interval settings. This will be addressed in two specific aims. Aim 1 will test and refine an algorithm based on non-invasive measures of breathing pattern, gas exchange and heart rate, obtained during low intensity exercise that predicts HF patient responsiveness to CRT device therapy. Aim 2 will test the ability of a similar algorithm, based on non-invasive cardiopulmonary gas exchange measures, to optimize atrial- ventricular synchrony and ventricular activation in HF patients receiving CRT device therapy relative to standard approaches for setting CRT intervals. This approach fills a significant need in this growing field, has the potential to reduce cost and individualize the approach to treatment. This proposal is designed to obtain initial exploratory data in order to test the techniques and further develop gas exchange algorithms/models to optimize the clinical practice of CRT. PUBLIC HEALTH RELEVANCE: The long term goal of our research program has been to understand the functional relationships between the cardiovascular and pulmonary systems, particularly as it relates to the heart failure population. This R21 application takes advantage of important cardio-pulmonary relationships and focuses on a novel approach to using non invasive pulmonary gas exchange measures obtained during slow treadmill walking to optimize atrioventricular (AV) and interventricular (V-V) intervals of cardiac resynchronization therapy (CRT) devices. This is important as CRT has become an important adjunct to medical therapy in the heart failure population, however, 25-30% of patients implanted have a poor or refractory response. This may be due to patient selection or current methods of setting device intervals. The premise of this proposal is that an algorithm of non invasive pulmonary gas exchange measures will not only help guide which patients would respond most positively to treatment, but will help to improve the response. This approach has the potential to improve patient health, simplify device optimization procedures, support an individualized approach to medicine and substantially impact CRT costs.